SYNAPTIC PHARMACOLOGY OF SINGLE SUBTHALAMIC NEURONS

单个底丘脑神经元的突触药理学

• 批准号: 6394140
• 负责人: STEVEN WILLIAM JOHNSON
• 金额: $ 18.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394140
• 关键词: 6 hydroxydopamine; Parkinson's disease; acetylcholine; action potentials; brain electrical activity; calcium flux; dihydroxyphenylalanine; disease /disorder model; dopamine; dopamine receptor; electrical property; experimental brain lesion; fluorescent dye /probe; glutamate receptor; immunocytochemistry; laboratory rat; neuropharmacology; receptor sensitivity; substantia nigra; subthalamus; synapses; tissue /cell culture; voltage /patch clamp; voltage gated channel

DESCRIPTION: (adapted from applicant's abstract) Electrophysiological studies will be conducted in rat brain slices to examine the characteristics of excitatory and inhibitory inputs to subthalamic neurons. Recordings in normal rats will be compared to those of rats treated with 6-hydroxydopamine (6-OHDA) and levodopa-treated animals, which will allow insight into Parkinson's disease. Specific aim 1 is devoted to characterization of voltage-dependent currents and effects of dopamine on membrane properties of subthalamic neurons in vitro. These studies will address the hypothesis that prolonged stimulation of subthalamic neurons reduces their activity because of persistent inactivation of voltage-gated calcium currents or desensitization of glutamate receptors. This hypothesis will specifically address how stimulation of this region "deep brain stimulation "may yield a clinical effect. Specific aim 2 will examine the effects of dopamine, ACh, and other transmitters on synaptic currents in both subthalamic and substantia nigra - reticulata neurons. The choice of dopamine and acetylcholine is logical given that these transmitters are likely to have effects normally. There is a specific hypothesis to be addressed, that is, chronic dopamine depletion and levodopa treatment, akin to Parkinonism, would alter receptor pharmacology. The manner that the experiment will address this hypothesis is not as clear as in specific aim 1. Specific aim 3 will identify ionic mechanisms that are responsible for burst firing in subthalamic neurons. Modulation by dopaminergic manipulations will be examined also. The importance of understanding burst firing is that this type of activity is more likely than single discharge to influence target neurons. Understanding the output of the subthalamic nucleus will clearly have relevance for understanding movement disorders and Parkinsonism. Specific aim 4 is based on previous studies showing that dopamine depletion/levodopa treatment both have chronic effects on GABA and muscarinic receptors in the basal ganglia. Thus it is hypothesized that this treatment will influence the synaptic potentials in both the subthalamic and substantia nigra- reticulata neurons. Therefore, rats which are lesioned with 6-hydroxydopamine or treated with levodopa will be examined in vitro for synaptic changes in the subthalamic nucleus and substantia nigra-reticulata.

描述：（改编自申请人的摘要）电生理研究将在大鼠脑切片中进行，以检查丘脑下神经元的兴奋性和抑制性输入的特征。 将正常大鼠的记录与接受6-羟基多巴胺（6-OHDA）和左旋多巴治疗的动物治疗的大鼠的记录进行比较，这将使您深入了解帕金森氏病。特定的目标1致力于表征依赖电压的电流以及多巴胺对体外丘脑神经元膜特性的影响。 这些研究将解决以下假设：由于电压门控钙电流持续失活或谷氨酸受体脱敏，因此长时间丘脑神经元的刺激会降低其活性。 该假设将特别解决该区域“深脑刺激”的刺激如何产生临床作用。具体的目标2将检查多巴胺，ACH和其他发射机对丘脑和底膜下nigra -nigra -nigra -nigiculata神经元中的突触电流的影响。 鉴于这些发射器可能有正常作用，多巴胺和乙酰胆碱的选择是逻辑上的。 有一个特定的假设要解决，即，类似于帕克尼奥主义的慢性多巴胺耗竭和左旋多巴治疗将改变受体药理学。实验解决这一假设的方式不像特定目的1中那样清楚。特定目标3将识别导致丘脑下神经元中爆发的离子机制。 还将检查通过多巴胺能操纵的调节。 理解爆发的重要性在于，这种活动比单个放电更有可能影响目标神经元。 了解丘脑下核的输出显然与理解运动障碍和帕金森氏症有关。具体目标4基于先前的研究表明，多巴胺耗竭/左旋多巴治疗都对基底神经节中的GABA和毒蕈碱受体具有慢性影响。 因此，假设这种治疗方法将影响丘脑下和黑质神经元的突触潜力。 因此，将在体外检查用6-羟基多巴胺或用左旋多巴治疗的大鼠在体外检查丘脑下核和底虫nigra-续航的突触变化。